Lantibiotics are ribosomally synthesized and posttranslationally modified polycyclic peptides containing thioether bridges (1). The crosslinks are made in a two-step process of first dehydration of Ser and Thr residues to the corresponding dehydro amino acids dehydroalanine (Dha) and dehydrobutyrine (Dhb), and subsequent conjugate addition of the thiol of Cys to the dehydro amino acids. The N-terminus of the precursor peptide is termed the leader peptide and is removed in the final step of maturation whereas the C-terminus is designated the core peptide and is converted into the lantibiotic (2). For class I lantibiotics, dehydration and cyclization are carried out by two different enzymes, generically called LanB and LanC, whereas for class II lantibiotics, both reactions are performed by a bifunctional enzyme (LanM). The class I lantibiotic nisin, the most extensively studied member of the lantibiotic family, was first approved for use as a food preservative to combat food-borne pathogens in 1969 and is currently used in over 50 countries (3). Despite this widespread use, very little resistance against nisin has been reported, possible owing to its mode of action. Nisin binds to the pyrophosphate group of lipid II, thereby preventing its use as an essential intermediate in bacterial cell wall biosynthesis (4-6). In addition, the lipid II-nisin complex forms long-lived pores resulting in depolarization of the membrane (7, 8). In comparison to other modes of action, it may be more challenging for a target organism to change the structure of an advanced intermediate such as lipid II that is biosynthesized in 10 steps (9, 10), than to acquire other resistance mechanisms such as efflux pumps and enzyme mutations. These latter mechanisms will not affect nisin as it acts on the outside of the bacterial cell and has a small molecule as target.
In addition to its use as a food preservative, the Center for Veterinary Medicine of the U.S. Food and Drug Administration recently ruled positively on application of nisin for intramammary treatment of subclinical mastitis in dairy cattle. After approval of the pending New Animal Drug Application, a nisin-containing product would allow treatment of bovine mastitis with a zero milk discard time and zero meat withdrawal period (i.e. milk and/or meat from treated cattle would not have to be discarded). One drawback that has been noted for nisin is its limited stability at pH 7 (11-15). Hence, more stable analogs may prove more effective.